Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome

Abstract

Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

“…However, increased number of entries at 11 months of age in Ts65Dn mice is close to statistical significance. Significant differences in the number of entries have been reported recently in aged Ts65Dn (Lysenko et al, 2014). However, our longitudinal study demonstrates that the number of entries for Ts65Dn animals remain similar at 2 and 11 months of age.…”

Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome

“…Though we failed to detect an effect of increased Kcnj6 dose on working memory as examined in the Y-maze, we did observe normalization of exploratory behavior during Y-maze testing, suggesting that Kcnj6 dose may play a role in exploration in the context of this test. We note that deficient working memory has not responded to most of the treatments restoring long-term memory in genetic models of DS (Kleschevnikov et al, 2012a; Lysenko et al, 2014). A likely explanation is that the deficiency in working memory is genetically and mechanistically distinct from the deficits in long-term memory and synaptic plasticity, as studied herein.…”

“…To assess the impact of Kcnj6 dose on long-term memory, we used the novel object recognition test with a retention period of 24 h. In prior studies, this test consistently demonstrated impairment of long-term memory in Ts65Dn mice (Fernandez et al, 2007; Kleschevnikov et al, 2012a; Lysenko et al, 2014). On average, mice of all genotypes spent equal time investigating objects during both the acquisition ( p = 0.16–0.39) and testing ( p = 0.3–0.75; Fig.…”

Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

“…Elevated spontaneous locomotor activity was reported extensively in the Ts65Dn mice18313335127128. We analyzed the exploratory behavior and general locomotor activity in an open field arena.…”

“…Elevated spontaneous locomotor activity has been documented both in young and old Ts65Dn mice18313335127128. Also in DS individuals, hyperkinetic and hyperactivity disorders are common158159.…”